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Activation of the receptor for advanced glycation end products (RAGE) is associated with long-term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction.Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age-dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 ± 13.8 vs. 94.5 ± 14.9 mmHg/µL, P=0.04) and development of increased LV diastolic chamber stiffness (0.18 ± 0.05 vs. 0.27 ± 0.07 mmHg, P=0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCβ) to the adult isoform (MHCα).Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.